SmartCells has developed Smartlnsulin, a once-a-day, injectable formulation of insulin for the treatment of diabetes. True glycemic control requires treatments that provide plasma glucose-regulated insulin replacement. Smartlnsulin, which senses and responds to altered serum glucose levels in a clinically relevant way, directly addresses this need. Unlike pump- and cell-based systems, Smartlnsulin is a "smart" nanostructured material that self-assembles from two biomolecular building blocks: a glycosylated insulin polymer conjugate (IPC) and a multimeric glucose-binding molecule (GBM). In this proposal, we seek to replace our proof-of-concept formulation with a safer, non-immunogenic, synthetic GBM constructed from ribonucleic acid (RNA)-based aptamers through the following specific aims: -Develop nuclease-resistant RNA-based aptamers that bind glucose -Synthesize multimeric RNA aptamers from monomeric constructs using a self-assembly process -Demonstrate that RNA aptamers form gels with IPCs and dissolve at physiologically relevant glucose concentrations. The impacts on public health as a result of this project are potentially significant. Poor glycemic control has been shown to cause a host of diabetic complications including retinopathy, neuropathy, nephropathy, and increased prevalence of heart disease and stroke, which result in over $54 billion annually in medical costs. The landmark Diabetes Control and Complications Trial (DCCT) and the UK Prospective Diabetes Study (UKPDS), have clinically proven that tighter glycemic control, as measured by lower glycosylated hemoglobin A1c (HbA1c) levels, significantly reduces the incidence of these complications. Thus, Smartlnsulin seeks to provide tighter glycemic control, lowered HbA1c levels, and decreased incidence of diabetic complications.